title: CD40-independent help by memory CD4 T cells induces pathogenic alloantibody but does not lead to long-lasting humoral immunity.
abstract: CD40/CD154 interactions are essential for productive antibody responses to T-dependent antigens. Memory CD4 T cells express accelerated helper functions and are less dependent on costimulation when compared with naïve T cells. Here, we report that donor-reactive memory CD4 T cells can deliver help to CD40-deficient B cells and induce high titers of IgG alloantibodies that contribute to heart allograft rejection in CD40-/- heart recipients. While cognate interactions between memory helper T and B cells are crucial for CD40-independent help, this process is not accompanied by germinal center formation and occurs despite inducible costimulatory blockade. Consistent with the extrafollicular nature of T/B cell interactions, CD40-independent help fails to maintain stable levels of serum alloantibody and induce differentiation of long-lived plasma cells and memory B cells. In summary, our data suggest that while CD40-independent help by memory CD4 T cells is sufficient to induce high levels of pathogenic alloantibody, it does not sustain long-lasting anti-donor humoral immunity and B cell memory responses. This information may guide the future use of CD40/CD154 targeting therapies in transplant recipients containing donor-reactive memory T cells.
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Service de Transplantation Rénale, Hôpital Necker, 75743 Paris Cedex 15, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gorbacheva
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Fan
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D056724:Immunity, Humoral / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D014019:Tissue Donors
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007518:Isoantibodies; D023201:CD40 Ligand
keywords: Alloantibody; CD40 costimulation; memory T cells